Convincing evidence suggests that focal adhesion kinase (FAK), a cytoplasmic, non-receptor tyrosine kinase, plays an essential role in cell-matrix signal transduction pathways (Clark and Brugge 1995, Science 268: 233-239) and its aberrant activation is associated with an increase in the metastatic potential of tumors (Owens et al. 1995, Cancer Research 55: 2752-2755). Selective inhibitors of certain non-receptor tyrosine kinases, such as FAK (focal adhesion kinase), Ick, sre, abl or serine/threonine kinases (e.g., cyclin dependent kinases), are useful in the treatment of abnormal cell growth, in particular cancer, in mammals. FAK is also known as the Protein-Tyrosine Kinase 2, PTK2. Compounds, compound combinations, compositions, and methods for inhibiting FAK in a subject are therefore desirable. FAK expression and/or activity has been reported to be upregulated in a range of malignancies, including cancers of the thyroid, prostate, cervix, colon, rectum, oral epithelium, ovary, and breast.
Components of the Ras/Raf/MEK/ERK signal transduction pathway also represent opportunities for the treatment of abnormal cell growth, e.g., cancer. MEK proteins are the primary downstream targets of Raf. The MEK family of genes consists of five genes: MEK1, MEK2, MEK3, MEK4, and MEK5. The MEK proteins belong to a family of dual-specificity kinases that have both serine/threonine and tyrosine kinase activity. MEK inhibitors have shown potential therapeutic benefit, for example, for inhibiting human tumor growth in nude mouse xenografts (Yeh, T. et al, Proceedings of the American Association of Cancer Research 2004, 45, Abs 3889). The MEK/ERK pathway has also been implicated in the self-renewal of cancer stem cells in breast and prostate cancer (Balko et al, Cancer Research 2013; Rybak et al, PLoS One 2013).